Coatings with crystallized active agent(s) and methods

ABSTRACT

The present invention relates to coatings with crystallized active agent(s) and related methods. In an embodiment, the invention includes a method for coating a medical device including selecting a solvent and a polymer, selecting a concentration of an active agent of at least a certain amount of saturation, forming a coating composition having the selected concentration of the active agent, and applying the coating composition to the medical device. In an embodiment, the invention includes an elution control coating disposed on a medical device, the elution control coating including a polymer, and an active agent, wherein the active agent is at least about 80% crystallized within one week of being disposed on the medical device. In an embodiment, the invention includes a method for enhancing the formation of active agent crystals within a coating layer including forming a coating solution and adjusting the concentration of the active agent in the coating solution to reach some percentage of the active agent saturation point. In an embodiment, the invention includes a method of enhancing crystallization of an active agent, the method including forming a coating solution comprising a polymer, an active agent, and a solvent; applying the coating solution to a substrate; and increasing the rate of active agent nucleation within the coating.

This application is a continuation of U.S. application Ser. No.12/636,164, filed Dec. 11, 2009, which is a continuation of U.S.application Ser. No. 11/295,167, filed Dec. 6, 2005 which claims thebenefit of U.S. Provisional Application No. 60/634,070, filed Dec. 7,2004, the contents of which are herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to coating compositions and relatedmethods. More specifically, the present invention relates to coatingswith crystallized active agent(s) and related methods.

BACKGROUND OF THE INVENTION

Therapeutic benefits can be achieved in some instances by providing anactive agent to a specific target tissue, instead of systemically. Thisis because the effect of the agent on the target tissue can be maximizedwhile limiting side effects on other tissues. Therapeutic benefits canalso be achieved by providing an active agent to a subject in a mannerthat extends the time over which the active agent is released. Oneapproach to providing these benefits is to use a coating systemcontaining an active agent on a medical device.

Predictability and consistency of the elution rate of an active agentfrom a coating or material on devices is of importance, particularly inthe clinical context. Specifically, in some applications it can beproblematic if two devices manufactured in the same batch havesignificantly different elution rates, or if the elution rates varysignificantly between separate batches. Finally, shelf stability ofcoated devices is of significance as an excessively short shelf-life mayraise costs associated with maintaining an inventory sufficient to meetdemand.

Accordingly, there is a need for coatings and methods of coatingproviding consistent elution rates. There is also a need for coatingsand methods of coating providing adequate shelf-stability.

SUMMARY OF THE INVENTION

The present invention relates to coatings with crystallized activeagent(s) and related methods. In an embodiment, the invention includes amethod for coating a medical device including selecting a solvent and apolymer, selecting a concentration of an active agent of at least acertain amount of saturation, forming a coating composition having theselected concentration of the active agent, and applying the coatingcomposition to the medical device. In an embodiment, the inventionincludes an elution control coating disposed on a medical device, theelution control coating including a polymer, and an active agent,wherein the active agent is at least about 80% crystallized within oneweek of being disposed on the medical device. In an embodiment, theinvention includes a method for enhancing the formation of active agentcrystals within a coating layer including forming a coating solution andadjusting the concentration of the active agent in the coating solutionto reach some percentage of the active agent saturation point. In anembodiment, the invention includes a method of enhancing crystallizationof an active agent, the method including forming a coating solutioncomprising a polymer, an active agent, and a solvent; applying thecoating solution to a substrate; and increasing the rate of active agentnucleation within the coating.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a microscopic view of a coating on a device taken underpolarizing light.

FIG. 2 is a microscopic view of a coating on a device of FIG. 1 takenunder polarizing light four days later.

FIG. 3 is an image of the surface features of a coating on a devicetaken using scanning electron microscopy (SEM).

FIG. 4 is an image of the surface features of a coating on a devicetaken using SEM.

FIG. 5 is an image of a coating on a device taken using darkfieldmicroscopy.

FIG. 6 is an image of the surface features of a coating on a devicetaken using SEM.

FIG. 7 is an image of the surface features of a coating on a devicetaken using SEM.

FIG. 8 is an image of the surface features of a coating on a devicetaken using SEM.

FIG. 9 is an image of the surface features of a coating on a devicetaken using SEM.

FIG. 10 is a series of six images of two different coatings taken over aperiod of two weeks using polarized light optical microscopy.

FIG. 11 is a series of two images of two different coatings taken usingpolarized light optical microscopy at high magnification showing thedistinction in crystal sizes between the two different coatings.

While the invention is susceptible to various modifications andalternative forms, specifics thereof have been shown by way of exampleand drawings, and will be described in detail. It should be understood,however, that the invention is not limited to the particular embodimentsdescribed. On the contrary, the intention is to cover modifications,equivalents, and alternatives falling within the spirit and scope of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “solubility” refers to the amount of asubstance (called the solute) that can be dissolved in given quantity ofanother substance (called the solvent) at given environmentalconditions, such as at a given temperature.

As used herein, the term “saturated” shall refer to the conditionwherein a solvent cannot dissolve any more of a solute (such as an“active agent”) at a given temperature and pressure. As used herein, theterm saturated shall also include the condition of supersaturation.

As used herein, the term “supersaturated” shall refer to the conditionwhere more of a solute is dissolved in a solvent than is stable at agiven temperature. Supersaturation may occur in instances such as when asaturated solution is cooled down.

In some coating systems used for drug delivery, the coating is appliedto a substrate as a coating solution containing polymer(s), activeagent(s), and solvent(s). Typically, the solvents evaporate from thecoating solution during and/or after application to the substrate toform a coating layer or layers. In some cases, the active agentcrystallizes over a period of days, weeks, or even months. The finalextent of crystallization (e.g., the percentage of the total activeagent that eventually turns into a crystalline form) depends on manyfactors including the particular active agent being used, the polymersused, the amount of residual solvent, the presence of other componentssuch as additives or impurities, etc. In some cases, substantially allof the active agent crystallizes. In other cases, virtually none of theactive agent crystallizes. In still other cases, some percentage of theactive agent crystallizes while the rest remains non-crystalline (oramorphous).

Batch-to-batch consistency of active agent elution rates for coateddevices can be affected by the extent of crystallization. For someactive agents, elution of a crystalline form is slower than elution of anon-crystalline form. This is because solvation of the compoundgenerally occurs before the compound can be eluted and crystalline formsgenerally form solvates more slowly than otherwise similarnon-crystalline forms. Thus, for the sake of elution consistency, it isdesirable to have some degree of consistency regarding the totalpercentage of the active agent that crystallizes from batch to batch.Embodiments of the invention can increase elution consistency byenhancing the crystallization process resulting in more rapid anduniform crystallization within and across batches.

In addition, where the crystallization process occurs relatively slowly,such as over multiple days or weeks, the percentage of active agentcrystallizing is more likely to be affected by other variables such aspost-manufacturing temperature and humidity, and this can affect bothbatch-to-batch elution consistency as well as intra-batch elutionconsistency. For example, a device that is subject to relatively coldertransport and/or storage conditions between the time of manufacturingand end use may exhibit a greater degree of crystallization in contrastto a device manufactured as a part of the same batch but that wassubject to warmer transport and/or storage conditions. Embodiments ofthe invention can increase elution consistency by speeding up thecrystallization process resulting in devices that are less susceptibleto variations in transport and/or storage conditions.

In addition, active agents are more stable in a crystalline form. Thus,enhancing the crystallization process can enhance the stability ofactive agents in coatings. Embodiments of the invention can includecoatings with active agents having enhanced stability because they arein a crystalline form.

Sometimes, during the crystallization process that occurs after acoating solution is applied to a substrate, crystals form in a mannersuch that they break-through, or erupt from, the surface of the coating.If enough crystals erupt through the surface of the coating, theperformance of the coating may be compromised. For example, active agentthat is not covered by any coating material will elute off faster thanactive agent that is disposed within the coating material. Thus,crystals erupting through the surface can cause the initial elutionburst to be increased, potentially to an undesirable level. It isbelieved that the process of crystals erupting from the surface of acoating is related to average crystal size. Specifically, it is believedthat larger crystals erupt from the surface of a coating to a greaterextent than do smaller crystals. In many cases, a more rapidcrystallization process results in a smaller crystal size on averagethan does a slower crystallization process. Embodiments of the inventioncan increase the speed of the crystallization process resulting in theformation of smaller crystals that are less likely to erupt from thesurface of a coating than are larger crystals.

Crystallization involves the formation of a solid aggregate in which theplane faces intersect at definite angles and in which there is a regularinternal structure of the constituent chemical species. Nucleation isthe formation in a solution of a number of minute solid bodies, embryos,nuclei or seeds that then act as centers of crystallization. Nucleationmay occur spontaneously or it may be induced artificially. Nucleationcan be classified as either primary or secondary. Primary nucleationrefers to all cases of nucleation in systems that do not containcrystalline matter to start. Primary nucleation can be further dividedinto homogeneous primary nucleation, which is spontaneous primarynucleation, and heterogeneous primary nucleation which is primarynucleation induced by foreign particles. Secondary nucleation refers tonucleation induced by crystals. Crystallization depends on both thecondition of supersaturation (as defined above) and the process ofnucleation. Accordingly, crystallization can be enhanced or acceleratedby increasing the degree of supersaturation and/or enhancing thenucleation process.

In some embodiments of the invention, crystallization is enhanced byincreasing the degree of supersaturation or increasing the speed withwhich the coating solution becomes supersaturated during or afterapplication to a substrate. By way of example, it has been discoveredthat adjusting the concentration of an active agent in a coatingsolution to a point, by way of example to the saturation point, enhancesrapid crystal formation. For example, assuming a solution containingactive agent is at the limit of solubility, as soon as some solventstarts to evaporate, the remaining solvent becomes supersaturated withthe active agent. This rapid state of supersaturation causescrystallization to occur more rapidly and frequently more consistently.In an embodiment, the invention includes a method for coating a medicaldevice including selecting a solvent and a polymer, selecting aconcentration of an active agent of at least 80% of saturation in acomposition comprising the solvent and about 1.0 to about 99.0 wt. %polymer, combining the active agent, the polymer, and the solvent toform a coating composition having the selected concentration of theactive agent, and applying the coating composition to the medicaldevice. In an embodiment, the invention includes a method for rapidlycrystallizing an active agent in a coating layer including combining apolymer, an active agent, and a solvent to form a coating solutionhaving between 5 mg/ml and 200 mg/ml total solids concentration,adjusting the concentration of the active agent in the coating solutionto reach at least 80% of the active agent saturation point, applying thecoating solution to a device, and evaporating the solvent to formcrystals of the active agent.

Embodiments of the invention can include coatings that can be used tocontrol the elution rate of active agents therefrom. In an embodiment,the invention includes an elution control coating disposed on a medicaldevice, the elution control coating including a polymer, and an activeagent, wherein the active agent is at least about 80% crystallizedwithin one week of being disposed on the medical device. In anembodiment, the active agent is at least about 90% crystallized withinone week of being disposed on the medical device. The active agent canbe at least about 95% crystallized within one week of being disposed onthe medical device. The active agent can be at least about 95%crystallized within one day of being disposed on the medical device.

In some embodiments, supersaturation is increased by addition of acomponent to a coating solution that decreases solubility of the activeagent in the solvent.

In some embodiments of the invention, crystallization is enhanced byenhancing the nucleation process. By way of example, in someembodiments, nucleation is enhanced by seeding the coating solution asit is applied with crystals of the active agent. In other embodiments,nucleation is enhanced by the addition of foreign particles to thecoating solution that function to trigger heterogeneous primarynucleation.

Coating Composition:

Coating compositions used in embodiments of the invention can includecomponents such as polymer(s), solvent(s), active agent(s), additives,etc. In an embodiment, the coating composition is saturated with activeagent or near saturation. In an embodiment, the concentration of activeagent in the coating composition is at least 60% of saturation limit atan ambient temperature. In an embodiment, the concentration of activeagent in the coating composition is at least 70% of the saturation limitat an ambient temperature. In an embodiment, the concentration of activeagent in the coating composition is at least 80% of the saturation limitat an ambient temperature. In an embodiment, the concentration of activeagent in the coating composition is at least 90% of the saturation limitat an ambient temperature. In an embodiment, the concentration of activeagent in the coating composition is at least 95% of the saturation limitat an ambient temperature. In an embodiment, the concentration of activeagent in the coating composition is at least 99% of the saturation limitat an ambient temperature. In an embodiment, the concentration of activeagent in the coating composition is at least 100% of the saturationlimit at an ambient temperature.

In some embodiments, the coating solution can be characterized withrespect to the total amount of solids in the composition including theactive agent and polymer(s). In an embodiment, the total amount ofsolids concentration in the solution is between 5 mg/ml and 200 mg/ml.In an embodiment, the total solids concentration is between 10 mg/ml and80 mg/ml. In an embodiment, the total solids concentration is between 20mg/ml and 60 mg/ml. In an embodiment, the total solids concentration isbetween 30 mg/ml and 50 mg/ml. In an embodiment, the total solidsconcentration is about 40 mg/ml.

In some embodiments, the coating solution includes a first solvent and asecond solvent, wherein the active agent is insoluble or only sparinglysoluble in the first solvent but soluble or freely soluble in the secondsolvent. In an embodiment, the polymer(s) of the coating composition aresoluble in both the first and second solvent. One method of preparingthe coating composition with two solvents, wherein the active agent isonly soluble in one of them, includes mixing the polymer(s) with theparticular solvent that the active agent is insoluble or only sparinglysoluble in, then mixing the active agent with the other solvent, andfinally combining the two solutions in various proportions until it isdetermined what percentage of the first solvent causes the active agentto start precipitating out of the solution. A coating solution can thenbe prepared with a percentage of the first solvent that pushes theamount of active agent to the saturation limit for the relativeproportions of the two solvents being used.

The coating composition may also include other components. By way ofexample, the coating composition may include agents that aid in thenucleation process (homogenous or heterogenous) to enhancecrystallization. In an embodiment, the composition may include acomponent that serves as a seed. This component may include crystallizedactive agent or another compound that enhances the crystallizationprocess. In an embodiment, a component that triggers heterogeneousnucleation is deposited onto a substrate and then the coating solutionis deposited onto that component.

The coating composition may also include other components that enhancecrystallization. By way of example, the coating composition may includeother solvents that enhance crystallization of a particular activeagent.

Solvents:

Many different solvents can be used with embodiments of the presentinvention depending on the particular polymers and active agents used.Solvents can include water, alcohols (e.g., methanol, butanol, propanol,and isopropanol (isopropyl alcohol)), alkanes (e.g., halogenated orunhalogenated alkanes such as hexane and cyclohexane), amides (e.g.,dimethylformamide), ethers (e.g., THF and dioxolane), ketones (e.g.,methylethylketone), aromatic compounds (e.g., toluene and xylene),nitriles (e.g., acetonitrile) and esters (e.g., ethyl acetate). In anembodiment, the solvent is one in which a polymer component(s) forms atrue solution.

In an embodiment, the invention includes a first solvent and a secondsolvent, wherein the active agent is soluble or freely soluble in thefirst solvent but insoluble or only sparingly soluble in the secondsolvent. In an embodiment, the first solvent can be THF. In anembodiment, the second solvent can be toluene. In an embodiment, thefirst solvent has a higher vapor pressure than the second solvent and isthus more volatile than the second solvent.

Polymers

Coating solutions used in embodiments of the invention can include oneor more polymers. In an embodiment, the coating solution includes aplurality of polymers, including a first polymer and a second polymer.When the coating solution contains only one polymer, it can be either afirst or second polymer as described herein. As used herein, term“(meth)acrylate” when used in describing polymers shall mean the formincluding the methyl group (methacrylate) or the form without the methylgroup (acrylate).

Examples of suitable first polymers include poly(alkyl(meth)acrylates),and in particular, those with alkyl chain lengths from 2 to 8 carbons,and with molecular weights from 50 kilodaltons to 900 kilodaltons. Anexemplary first polymer is poly(n-butyl methacrylate) (pBMA). Suchpolymers are available commercially, e.g., from Aldrich, with molecularweights ranging from about 200,000 Daltons to about 320,000 Daltons, andwith varying inherent viscosity, solubility, and form (e.g., as crystalsor powder).

Examples of suitable first polymers also include polymers selected fromthe group consisting of poly(aryl(meth)acrylates),poly(aralkyl(meth)acrylates), and poly(aryloxyalkyl(meth)acrylates).Such terms are used to describe polymeric structures wherein at leastone carbon chain and at least one aromatic ring are combined withacrylic groups, typically esters, to provide a composition. Inparticular, exemplary polymeric structures include those with arylgroups having from 6 to 16 carbon atoms and with weight averagemolecular weights from about 50 to about 900 kilodaltons. Suitablepoly(aralkyl(meth)acrylates), poly(arylalky(meth)acrylates) orpoly(aryloxyalkyl (meth)acrylates) can be made from aromatic estersderived from alcohols also containing aromatic moieties. Examples ofpoly(aryl(meth)acrylates) include poly(9-anthracenyl methacrylate),poly(chlorophenylacrylate), poly(methacryloxy-2-hydroxybenzophenone),poly(methacryloxybenzotriazole), poly(naphthylacrylate) and-methacrylate), poly(4-nitrophenyl acrylate), poly(pentachloro(bromo,fluoro)acrylate) and -methacrylate), and poly(phenyl acrylate) and-methacrylate). Examples of poly(aralkyl(meth)acrylates) includepoly(benzyl acrylate) and -methacrylate), poly(2-phenethyl acrylate) and-methacrylate, and poly(1-pyrenylmethyl methacrylate). Examples ofpoly(aryloxyalkyl(meth)acrylates) include poly(phenoxyethyl acrylate)and -methacrylate), and poly(polyethylene glycol phenyl ether acrylates)and -methacrylates with varying polyethylene glycol molecular weights.

Examples of suitable second polymers are available commercially andinclude poly(ethylene-co-vinyl acetate) (pEVA) having vinyl acetateconcentrations of between about 10% and about 50% (12%, 14%, 18%, 25%,33% versions are commercially available), in the form of beads, pellets,granules, etc. pEVA co-polymers with lower percent vinyl acetate becomeincreasingly insoluble in typical solvents, whereas those with higherpercent vinyl acetate become decreasingly durable.

An exemplary polymer mixture for use in this invention includes mixturesof pBMA and pEVA. This mixture of polymers can be used with absolutepolymer concentrations (i.e., the total combined concentrations of bothpolymers in the coating material), of between about 0.25 wt. % and about99 wt. %. This mixture can also be used with individual polymerconcentrations in the coating solution of between about 0.05 wt. % andabout 99 wt. %. In one embodiment the polymer mixture includes pBMA witha molecular weight of from 100 kilodaltons to 900 kilodaltons and a pEVAcopolymer with a vinyl acetate content of from 24 to 36 weight percent.In an embodiment the polymer mixture includes pBMA with a molecularweight of from 200 kilodaltons to 400 kilodaltons and a pEVA copolymerwith a vinyl acetate content of from 24 to 36 weight percent. Theconcentration of the active agent or agents dissolved or suspended inthe coating mixture can range from 0.01 to 99 percent, by weight, basedon the weight of the final coating material.

Second polymers of the invention can also comprise one or more polymersselected from the group consisting of (i)poly(alkylene-co-alkyl(meth)acrylates, (ii) ethylene copolymers withother alkylenes, (iii) polybutenes, (iv) diolefin derived non-aromaticpolymers and copolymers, (v) aromatic group-containing copolymers, and(vi) epichlorohydrin-containing polymers. First polymers of theinvention can also comprise a polymer selected from the group consistingof poly(alkyl(meth)acrylates) and poly(aromatic(meth)acrylates), where“(meth)” will be understood by those skilled in the art to include suchmolecules in either the acrylic and/or methacrylic form (correspondingto the acrylates and/or methacrylates, respectively).

Poly(alkylene-co-alkyl(meth)acrylates) include those copolymers in whichthe alkyl groups are either linear or branched, and substituted orunsubstituted with non-interfering groups or atoms. Such alkyl groupscan comprise from 1 to 8 carbon atoms, inclusive. Such alkyl groups cancomprise from 1 to 4 carbon atoms, inclusive. In an embodiment, thealkyl group is methyl. In some embodiments, copolymers that include suchalkyl groups can comprise from about 15% to about 80% (wt) of alkylacrylate. When the alkyl group is methyl, the polymer contains fromabout 20% to about 40% methyl acrylate in some embodiments, and fromabout 25% to about 30% methyl acrylate in a particular embodiment. Whenthe alkyl group is ethyl, the polymer contains from about 15% to about40% ethyl acrylate in an embodiment, and when the alkyl group is butyl,the polymer contains from about 20% to about 40% butyl acrylate in anembodiment.

Alternatively, second polymers for use in this invention can compriseethylene copolymers with other alkylenes, which in turn, can includestraight and branched alkylenes, as well as substituted or unsubstitutedalkylenes. Examples include copolymers prepared from alkylenes thatcomprise from 3 to 8 branched or linear carbon atoms, inclusive. In anembodiment, copolymers prepared from alkylene groups that comprise from3 to 4 branched or linear carbon atoms, inclusive. In a particularembodiment, copolymers prepared from alkylene groups containing 3 carbonatoms (e.g., propene). By way of example, the other alkylene is astraight chain alkylene (e.g., 1-alkylene). Exemplary copolymers of thistype can comprise from about 20% to about 90% (based on moles) ofethylene. In an embodiment, copolymers of this type comprise from about35% to about 80% (mole) of ethylene. Such copolymers will have amolecular weight of between about 30 kilodaltons to about 500kilodaltons. Exemplary copolymers are selected from the group consistingof poly(ethylene-co-propylene), poly(ethylene-co-1-butene),polyethylene-co-1-butene-co-1-hexene) and/or poly(ethylene-co-1-octene).

“Polybutenes” suitable for use in the present invention includespolymers derived by homopolymerizing or randomly interpolymerizingisobutylene, 1-butene and/or 2-butene. The polybutene can be ahomopolymer of any of the isomers or it can be a copolymer or aterpolymer of any of the monomers in any ratio. In an embodiment, thepolybutene contains at least about 90% (wt) of isobutylene or 1-butene.In a particular embodiment, the polybutene contains at least about 90%(wt) of isobutylene. The polybutene may contain non-interfering amountsof other ingredients or additives, for instance it can contain up to1000 ppm of an antioxidant (e.g., 2,6-di-tert-butyl-methylphenol). Byway of example, the polybutene can have a molecular weight between about150 kilodaltons and about 1,000 kilodaltons. In an embodiment, thepolybutene can have between about 200 kilodaltons and about 600kilodaltons. In a particular embodiment, the polybutene can have betweenabout 350 kilodaltons and about 500 kilodaltons. Polybutenes having amolecular weight greater than about 600 kilodaltons, including greaterthan 1,000 kilodaltons are available but are expected to be moredifficult to work with.

Additional alternative second polymers include diolefin-derived,non-aromatic polymers and copolymers, including those in which thediolefin monomer used to prepare the polymer or copolymer is selectedfrom butadiene (CH₂═CH—CH═CH₂) and/or isoprene (CH₂═CH—C(CH₃)═CH₂). Inan embodiment, the polymer is a homopolymer derived from diolefinmonomers or is a copolymer of diolefin monomer with non-aromaticmono-olefin monomer, and optionally, the homopolymer or copolymer can bepartially hydrogenated. Such polymers can be selected from the groupconsisting of polybutadienes prepared by the polymerization of cis-,trans- and/or 1,2-monomer units, or from a mixture of all threemonomers, and polyisoprenes prepared by the polymerization of cis-1,4-and/or trans-1,4-monomer units. Alternatively, the polymer is acopolymer, including graft copolymers, and random copolymers based on anon-aromatic mono-olefin monomer such as acrylonitrile, and analkyl(meth)acrylate and/or isobutylene. In an embodiment, when themono-olefin monomer is acrylonitrile, the interpolymerized acrylonitrileis present at up to about 50% by weight; and when the mono-olefinmonomer is isobutylene, the diolefin is isoprene (e.g., to form what iscommercially known as a “butyl rubber”). Exemplary polymers andcopolymers have a molecular weight between about 150 kilodaltons andabout 1,000 kilodaltons. In an embodiment, polymers and copolymers havea molecular weight between about 200 kilodaltons and about 600kilodaltons.

Additional alternative second polymers include aromatic group-containingcopolymers, including random copolymers, block copolymers and graftcopolymers. In an embodiment, the aromatic group is incorporated intothe copolymer via the polymerization of styrene. In a particularembodiment, the random copolymer is a copolymer derived fromcopolymerization of styrene monomer and one or more monomers selectedfrom butadiene, isoprene, acrylonitrile, a C₁-C₄ alkyl(meth)acrylate(e.g., methyl methacrylate) and/or butene. Useful block copolymersinclude copolymer containing (a) blocks of polystyrene, (b) blocks of anpolyolefin selected from polybutadiene, polyisoprene and/or polybutene(e.g., isobutylene), and (c) optionally a third monomer (e.g., ethylene)copolymerized in the polyolefin block. The aromatic group-containingcopolymers contain about 10% to about 50% (wt.) of polymerized aromaticmonomer and the molecular weight of the copolymer is from about 300kilodaltons to about 500 kilodaltons. In an embodiment, the molecularweight of the copolymer is from about 100 kilodaltons to about 300kilodaltons.

Additional alternative second polymers include epichlorohydrinhomopolymers and poly(epichlorohydrin-co-alkylene oxide) copolymers. Inan embodiment, in the case of the copolymer, the copolymerized alkyleneoxide is ethylene oxide. By way of example, epichlorohydrin content ofthe epichlorohydrin-containing polymer is from about 30% to 100% (wt).In an embodiment, epichlorohydrin content is from about 50% to 100%(wt). In an embodiment, the epichlorohydrin-containing polymers have amolecular weight from about 100 kilodaltons to about 300 kilodaltons.

In an embodiment, polymers of the invention include hydrophobicpolymers. One method of defining the hydrophobicity of a polymer is bythe solubility parameter (or Hildebrand parameter) of the polymer. Thesolubility parameter describes the attractive strength between moleculesof the material. The solubility parameter is represented by Equation 1:

δ=(ΔE ^(v) /V)^(1/2)

where δ=solubility parameter ((cal/cm³)^(1/2))

ΔE^(v)=energy of vaporization (cal)

V=molar volume (cm³)

Solubility parameters cannot be calculated for polymers from heat ofvaporization data because of their nonvolatility. Accordingly,solubility parameters must be calculated indirectly. One method involvesidentifying solvents in which a polymer dissolves without a change inheat or volume and then defining the solubility parameter of the polymerto be the same as the solubility parameters of the identified solvents.A more complete discussion of solubility parameters and methods ofcalculating the same can be found in Brandup et al., Polymer Handbook,4th Ed., John Wiley & Sons, N.Y. (1999) beginning at VII p. 675.

As a general rule, the value of the solubility parameter δ is inverselyproportional to the degree of hydrophobicity of a polymer. Thus,polymers that are very hydrophobic may have a low solubility parametervalue. This general proposition is particularly applicable for polymershaving a glass transition temperature below physiological temperature.In an embodiment, polymers used with the invention have a solubilityparameter less than about 11.0 (cal/cm³)^(1/2). In an embodimentpolymers used with the invention have a solubility parameter of lessthan about 10.0 (cal/cm³)^(1/2).

Polymers can also include a poly(ether ester) multiblock copolymer basedon poly(ethylene glycol) (PEG) and poly(butylene terephthalate) and canbe described by the following general structure:

[—(OCH₂CH₂)_(n)—O—C(O)—C₆H₄—C(O)-]x[-O—(CH₂)₄—O—C(O)—C₆H₄—C(O)-]y,

where —C₆H₄— designates the divalent aromatic ring residue from eachesterified molecule of terephthalic acid, n represents the number ofethylene oxide units in each hydrophilic PEG block, x represents thenumber of hydrophilic blocks in the copolymer, and y represents thenumber of hydrophobic blocks in the copolymer. n can be selected suchthat the molecular weight of the PEG block is between about 300 andabout 4000. X and y can be selected so that the multiblock copolymercontains from about 55% up to about 80% PEG by weight.

The block copolymer can be engineered to provide a wide array ofphysical characteristics (e.g., hydrophilicity, adherence, strength,malleability, degradability, durability, flexibility) and active agentrelease characteristics (e.g., through controlled polymer degradationand swelling) by varying the values of n, x and y in the copolymerstructure. Degradation of the copolymer does not create toxicdegradation products or an acid environment, and its hydrophilic natureconserves the stability of labile active agents, such as proteins (e.g.,lysozymes).

Polymers of the invention also include biodegradable polymers. Suitablebiodegradable polymeric materials are selected from: (a) non-peptidepolyamino polymers; (b) polyiminocarbonates; (c) amino acid-derivedpolycarbonates and polyarylates; and (d) poly(alkylene oxide) polymers.The biodegradable polymeric materials can break down to form degradationproducts that are non-toxic and do not cause a significant adversereaction from the body.

In an embodiment, the biodegradable polymeric material is composed of anon-peptide polyamino acid polymer. Suitable non-peptide polyamino acidpolymers are described, for example, in U.S. Pat. No. 4,638,045(“Non-Peptide Polyamino Acid Bioerodible Polymers,” Jan. 20, 1987).Generally speaking, these polymeric materials are derived from monomers,including two or three amino acid units having one of the following twostructures illustrated below:

wherein the monomer units are joined via hydrolytically labile bonds atnot less than one of the side groups R₁, R₂, and R₃, and where R₁, R₂,R₃ are the side chains of naturally occurring amino acids; Z is anydesirable amine protecting group or hydrogen; and Y is any desirablecarboxyl protecting group or hydroxyl. Each monomer unit comprisesnaturally occurring amino acids that are then polymerized as monomerunits via linkages other than by the amide or “peptide” bond. Themonomer units can be composed of two or three amino acids united througha peptide bond and thus comprise dipeptides or tripeptides. Regardlessof the precise composition of the monomer unit, all are polymerized byhydrolytically labile bonds via their respective side chains rather thanvia the amino and carboxyl groups forming the amide bond typical ofpolypeptide chains. Such polymer compositions are nontoxic, arebiodegradable, and can provide zero-order release kinetics for thedelivery of active agents in a variety of therapeutic applications.According to these aspects, the amino acids are selected from naturallyoccurring L-alpha amino acids, including alanine, valine, leucine,isoleucine, proline, serine, threonine, aspartic acid, glutamic acid,asparagine, glutamine, lysine, hydroxylysine, arginine, hydroxyproline,methionine, cysteine, cystine, phenylalanine, tyrosine, tryptophan,histidine, citrulline, ornithine, lanthionine, hypoglycin A, β-alanine,γ-amino butyric acid, alpha aminoadipic acid, canavanine, venkolic acid,thiolhistidine, ergothionine, dihydroxyphenylalanine, and other aminoacids well recognized and characterized in protein chemistry.

In an embodiment, the biodegradable polymeric material can be composedof polyiminocarbonates. Polyiminocarbonates are structurally related topolycarbonates, wherein imino groups (>C═NH) are present in the placesnormally occupied by carbonyl oxygen in the polycarbonates. Thus, thebiodegradable component can be formed of polyiminocarbonates havinglinkages

For example, one useful polyiminocarbonate has the general polymerstructural formula

wherein R is an organic divalent group containing a non-fused aromaticorganic ring, and n is greater than 1. Embodiments of the R group withinthe general formula above are exemplified by, but is not limited to thefollowing:

R Group

-   -   wherein R′ is lower alkene C₁ to C₆

-   -   wherein n is an integer equal to or greater than 1, X is a        hetero atom such as —O—, —S—, or a bridging group such as —NH—,        —S(═O)—, —SO₂—, —C(═O)—, —C(CH₃)₂—, —CH(CH₃)—,        —CH(CH₃)—CH₂—CH(CH₃)—,

Also, compounds of the general formula

can be utilized, wherein X is O, NH, or NR′″, wherein R′″ is a loweralkyl radical; and R″ is a divalent residue of a hydrocarbon includingpolymers such as a polyolefin, an oligoglycol or polyglycol such aspolyalkylene glycol ether, a polyester, a polyurea, a polyamine, apolyurethane, or a polyamide. Exemplary starting material for use inaccordance with these embodiments include diphenol compounds having theformula

and dicyanate compounds having the formula

with R₁ and R₂ being the same or different and being alkylene, arylene,alkylarylene or a functional group containing heteroatoms. Z₁, and Z₂can each represent one or more of the same or different radicalsselected from the group consisting of hydrogen, halogen, lower-alkyl,carboxyl, amino, nitro, thioether, sulfoxide, and sulfonyl. Each of Z₁and Z₂ can be hydrogen.

In an embodiment, the biodegradable polymeric material can be composedof various types of amino acid-derived polycarbonates and polyarylates.These amino acid-derived polycarbonates and polyarylates can be preparedby reacting certain amino acid-derived diphenol starting materials witheither phosgene or dicarboxylic acids, respectively. Exemplary aminoacid-derived diphenol starting materials for the preparation of theamino acid-derived polycarbonates and/or polyarylates of this embodimentare monomers that are capable of being polymerized to formpolyiminocarbonates with glass transition temperatures (“Tg's”)sufficiently low to permit thermal processing. The monomers according tothis embodiment are diphenol compounds that are amino acid esterderivatives having the formula shown below:

in which R₁ is an alkyl group containing up to 18 carbon atoms.

In yet another embodiment, the biodegradable polymeric material can becomposed of copolymers containing both hydrophilic poly(alkylene oxides)(PAO) and biodegradable sequences, wherein the hydrocarbon portion ofeach PAO unit contains from 1 to 4 carbon atoms, or 2 carbon atoms(i.e., the PAO is poly(ethylene oxide)). For example, usefulbiodegradable polymeric materials can be made of block copolymerscontaining PAO and amino acids or peptide sequences and contain one ormore recurring structural units independently represented by thestructure -L-R₁-L-R₂—, wherein R₁ is a poly(alkylene oxide), L is —O— or—NH—, and R₂ is an amino acid or peptide sequence containing twocarboxylic acid groups and at least one pendent amino group.

Other useful biodegradable polymeric materials are composed ofpolyarylate or polycarbonate random block copolymers that includetyrosine-derived diphenol monomers and poly(alkylene oxide), such as thepolycarbonate shown below:

wherein R₁ is —CH═CH— or (—CH₂—)_(j), in which j is 0 to 8; R₂ isselected from straight and branched alkyl and alkylaryl groupscontaining up to 18 carbon atoms and optionally containing at least oneether linkage, and derivatives of biologically and pharmaceuticallyactive compounds covalently bonded to the copolymer; each R₃ isindependently selected from alkylene groups containing 1 to 4 carbonatoms; y is between 5 and about 3000; and f is the percent molarfraction of alkylene oxide in the copolymer and ranges from about 0.01to about 0.99.

In some embodiments, pendent carboxylic acid groups can be incorporatedwithin the polymer bulk for polycarbonates, polyarylates, and/orpoly(alkylene oxide) block copolymers thereof, to further control therate of polymer backbone degradation and resorption.

Polymers used in embodiments of the invention can include polymers thatare components of elution control coatings. By way of example, U.S. Pat.No. 6,214,901 (Chudzik et al.) discloses polymers used in bioactiveagent release coatings, the contents of which is herein incorporated byreference.

Active Agents

Coating solutions used with methods of the invention can contain one ormore active agents. As used herein, the term “active agent” means acompound that has a particular desired activity. For example, an activeagent can be a therapeutic compound that exerts a specific activity on asubject. In some embodiments, active agent will, in turn, refer to apeptide, protein, carbohydrate, nucleic acid, lipid, polysaccharide orcombinations thereof, or synthetic inorganic or organic molecule, thatcauses a desired biological effect when administered in vivo to ananimal, including but not limited to birds and mammals, includinghumans. In some embodiments, the active agent can be a bioactive agent.Active agents can have many different types of elution profiles.

Active agents useful according to the invention include substances thatpossess desirable therapeutic characteristics for application to theimplantation site. Active agents useful in the present invention caninclude many types of therapeutics including thrombin inhibitors,antithrombogenic agents, thrombolytic agents, fibrinolytic agents,anticoagulants, anti-platelet agents, vasospasm inhibitors, calciumchannel blockers, steroids, vasodilators, anti-hypertensive agents,antimicrobial agents, antibiotics, antibacterial agents, antiparasiteand/or antiprotozoal solutes, antiseptics, antifungals, angiogenicagents, anti-angiogenic agents, inhibitors of surface glycoproteinreceptors, antimitotics, microtubule inhibitors, antisecretory agents,actin inhibitors, remodeling inhibitors, antisense nucleotides,anti-metabolites, miotic agents, anti-proliferatives, anticancerchemotherapeutic agents, anti-neoplastic agents, antipolymerases,antivirals, anti-AIDS substances, anti-inflammatory steroids ornon-steroidal anti-inflammatory agents, analgesics, antipyretics,immunosuppressive agents, immunomodulators, growth hormone antagonists,growth factors, radiotherapeutic agents, peptides, proteins, enzymes,extracellular matrix components, ACE inhibitors, free radicalscavengers, chelators, anti-oxidants, photodynamic therapy agents, genetherapy agents, anesthetics, immunotoxins, neurotoxins, opioids,dopamine agonists, hypnotics, antihistamines, tranquilizers,anticonvulsants, muscle relaxants and anti-Parkinson substances,antispasmodics and muscle contractants, anticholinergics, ophthalmicagents, antiglaucoma solutes, prostaglandins, antidepressants,antipsychotic substances, neurotransmitters, anti-emetics, imagingagents, specific targeting agents, and cell response modifiers.

More specifically, in embodiments the active agent can include heparin,covalent heparin, synthetic heparin salts, or another thrombininhibitor; hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginylchloromethyl ketone, or another antithrombogenic agent; urokinase,streptokinase, a tissue plasminogen activator, or another thrombolyticagent; a fibrinolytic agent; a vasospasm inhibitor; a calcium channelblocker, a nitrate, nitric oxide, a nitric oxide promoter, nitric oxidedonors, dipyridamole, or another vasodilator; HYTRIN® or otherantihypertensive agents; a glycoprotein IIb/IIIa inhibitor (abciximab)or another inhibitor of surface glycoprotein receptors; aspirin,ticlopidine, clopidogrel or another antiplatelet agent; colchicine oranother antimitotic, or another microtubule inhibitor; dimethylsulfoxide (DMSO), a retinoid, or another antisecretory agent;cytochalasin or another actin inhibitor; cell cycle inhibitors;remodeling inhibitors; deoxyribonucleic acid, an antisense nucleotide,or another agent for molecular genetic intervention; methotrexate, oranother antimetabolite or antiproliferative agent; tamoxifen citrate,TAXOL®, paclitaxel, or the derivatives thereof, rapamycin (or otherrapalogs e.g. ABT-578 or sirolimus), vinblastine, vincristine,vinorelbine, etoposide, tenopiside, dactinomycin (actinomycin D),daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone,bleomycin, plicamycin (mithramycin), mitomycin, mechlorethamine,cyclophosphamide and its analogs, chlorambucil, ethylenimines,methylmelamines, alkyl sulfonates (e.g., busulfan), nitrosoureas(carmustine, etc.), streptozocin, methotrexate (used with manyindications), fluorouracil, floxuridine, cytarabine, mercaptopurine,thioguanine, pentostatin, 2-chlorodeoxyadenosine, cisplatin,carboplatin, procarbazine, hydroxyurea, morpholino phosphorodiamidateoligomer or other anti-cancer chemotherapeutic agents; cyclosporin,tacrolimus (FK-506), pimecrolimus, azathioprine, mycophenolate mofetil,mTOR inhibitors, or another immunosuppressive agent; cortisol,cortisone, dexamethasone, dexamethasone sodium phosphate, dexamethasoneacetate, dexamethasone derivatives, betamethasone, fludrocortisone,prednisone, prednisolone, 6U-methylprednisolone, triamcinolone (e.g.,triamcinolone acetonide), or another steroidal agent; trapidil (a PDGFantagonist), angiopeptin (a growth hormone antagonist), angiogenin, agrowth factor (such as vascular endothelial growth factor (VEGF)), or ananti-growth factor antibody (e.g., ranibizumab, which is sold under thetradename LUCENTIS®), or another growth factor antagonist or agonist;dopamine, bromocriptine mesylate, pergolide mesylate, or anotherdopamine agonist; ⁶⁰Co (5.3 year half life), ¹⁹²Ir (73.8 days), ³²P(14.3 days), ¹¹¹In (68 hours), ⁹⁰Y (64 hours), ⁹⁹Tc (6 hours), oranother radiotherapeutic agent; iodine-containing compounds,barium-containing compounds, gold, tantalum, platinum, tungsten oranother heavy metal functioning as a radiopaque agent; a peptide, aprotein, an extracellular matrix component, a cellular component oranother biologic agent; captopril, enalapril or another angiotensinconverting enzyme (ACE) inhibitor; angiotensin receptor blockers; enzymeinhibitors (including growth factor signal transduction kinaseinhibitors); ascorbic acid, alpha tocopherol, superoxide dismutase,deferoxamine, a 21-aminosteroid (lasaroid) or another free radicalscavenger, iron chelator or antioxidant; a ¹⁴C-, ³H-, ¹³¹I-, ³²P- or³⁶S-radiolabelled form or other radiolabelled form of any of theforegoing; an estrogen (such as estradiol, estriol, estrone, and thelike) or another sex hormone; AZT or other antipolymerases; acyclovir,famciclovir, rimantadine hydrochloride, ganciclovir sodium, Norvir,Crixivan, or other antiviral agents; 5-aminolevulinic acid,meta-tetrahydroxyphenylchlorin, hexadecafluorozinc phthalocyanine,tetramethyl hematoporphyrin, rhodamine 123 or other photodynamic therapyagents; an IgG2 Kappa antibody against Pseudomonas aeruginosa exotoxin Aand reactive with A431 epidermoid carcinoma cells, monoclonal antibodyagainst the noradrenergic enzyme dopamine beta-hydroxylase conjugated tosaporin, or other antibody targeted therapy agents; gene therapy agents;enalapril and other prodrugs; PROSCAR®, HYTRIN® or other agents fortreating benign prostatic hyperplasia (BHP); mitotane,aminoglutethimide, breveldin, acetaminophen, etodalac, tolmetin,ketorolac, ibuprofen and derivatives, mefenamic acid, meclofenamic acid,piroxicam, tenoxicam, phenylbutazone, oxyphenbutazone, nabumetone,auranofin, aurothioglucose, gold sodium thiomalate, a mixture of any ofthese, or derivatives of any of these.

Other biologically useful compounds that can also be included in thecoating include, but are not limited to, hormones, β-blockers,anti-anginal agents, cardiac inotropic agents, corticosteroids,analgesics, anti-inflammatory agents, anti-arrhythmic agents,immunosuppressants, anti-bacterial agents, anti-hypertensive agents,anti-malarials, anti-neoplastic agents, anti-protozoal agents,anti-thyroid agents, sedatives, hypnotics and neuroleptics, diuretics,anti-parkinsonian agents, gastro-intestinal agents, anti-viral agents,anti-diabetics, anti-epileptics, anti-fungal agents, histamineH-receptor antagonists, lipid regulating agents, muscle relaxants,nutritional agents such as vitamins and minerals, stimulants, nucleicacids, polypeptides, and vaccines.

Antibiotics are substances which inhibit the growth of or killmicroorganisms. Antibiotics can be produced synthetically or bymicroorganisms. Examples of antibiotics include penicillin,tetracycline, chloramphenicol, minocycline, doxycycline, vancomycin,bacitracin, kanamycin, neomycin, gentamycin, erythromycin, geldanamycin,geldanamycin analogs, cephalosporins, or the like. Examples ofcephalosporins include cephalothin, cephapirin, cefazolin, cephalexin,cephradine, cefadroxil, cefamandole, cefoxitin, cefaclor, cefuroxime,cefonicid, ceforanide, cefotaxime, moxalactam, ceftizoxime, ceftriaxone,and cefoperazone.

Antiseptics are recognized as substances that prevent or arrest thegrowth or action of microorganisms, generally in a nonspecific fashion,e.g., either by inhibiting their activity or destroying them. Examplesof antiseptics include silver sulfadiazine, chlorhexidine,glutaraldehyde, peracetic acid, sodium hypochlorite, phenols, phenoliccompounds, iodophor compounds, quaternary ammonium compounds, andchlorine compounds.

Antiviral agents are substances capable of destroying or suppressing thereplication of viruses. Examples of anti-viral agents includeα-methyl-1-adamantanemethylamine, hydroxy-ethoxymethylguanine,adamantanamine, 5-iodo-2′-deoxyuridine, trifluorothymidine, interferon,and adenine arabinoside.

Enzyme inhibitors are substances that inhibit an enzymatic reaction.Examples of enzyme inhibitors include edrophonium chloride,N-methylphysostigmine, neostigmine bromide, physostigmine sulfate,tacrine HCL, tacrine, 1-hydroxy maleate, iodotubercidin,p-bromotetramisole, 10-(α-diethylaminopropionyl)-phenothiazinehydrochloride, calmidazolium chloride,hemicholinium-3,3,5-dinitrocatechol, diacylglycerol kinase inhibitor I,diacylglycerol kinase inhibitor II, 3-phenylpropargylaminie,N-monomethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydrazineHCl, hydralazine HCl, clorgyline HCl, deprenyl HCl L(−), deprenyl HClD(+), hydroxylamine HCl, iproniazid phosphate,6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCl, quinacrineHCl, semicarbazide HCl, tranylcypromine HCl,N,N-diethylaminoethyl-2,2-di-phenylvalerate hydrochloride,3-isobutyl-1-methylxanthne, papaverine HCl, indomethacind,2-cyclooctyl-2-hydroxyethylamine hydrochloride,2,3-dichloro-α-methylbenzylamine (DCMB),8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride,p-aminoglutethimide, p-aminoglutethimide tartrate R(+),p-aminoglutethimide tartrate S(−), 3-iodotyrosine, alpha-methyltyrosineL(−), alpha-methyltyrosine D(−), cetazolamide, dichlorphenamide,6-hydroxy-2-benzothiazolesulfonamide, and allopurinol.

Anti-pyretics are substances capable of relieving or reducing fever.Anti-inflammatory agents are substances capable of counteracting orsuppressing inflammation. Examples of such agents include aspirin(salicylic acid), indomethacin, sodium indomethacin trihydrate,salicylamide, naproxen, colchicine, fenoprofen, sulindac, diflunisal,diclofenac, indoprofen and sodium salicylamide.

Local anesthetics are substances that have an anesthetic effect in alocalized region. Examples of such anesthetics include procaine,lidocaine, tetracaine and dibucaine.

Imaging agents are agents capable of imaging a desired site, e.g.,tumor, in vivo. Examples of imaging agents include substances having alabel that is detectable in vivo, e.g., antibodies attached tofluorescent labels. The term antibody includes whole antibodies orfragments thereof.

Cell response modifiers are chemotactic factors such as platelet-derivedgrowth factor (PDGF). Other chemotactic factors includeneutrophil-activating protein, monocyte chemoattractant protein,macrophage-inflammatory protein, SIS (small inducible secreted),platelet factor, platelet basic protein, melanoma growth stimulatingactivity, epidermal growth factor, transforming growth factor alpha,fibroblast growth factor, platelet-derived endothelial cell growthfactor, insulin-like growth factor, nerve growth factor, bonegrowth/cartilage-inducing factor (alpha and beta), and matrixmetalloproteinase inhibitors. Other cell response modifiers are theinterleukins, interleukin receptors, interleukin inhibitors,interferons, including alpha, beta, and gamma; hematopoietic factors,including erythropoietin, granulocyte colony stimulating factor,macrophage colony stimulating factor and granulocyte-macrophage colonystimulating factor; tumor necrosis factors, including alpha and beta;transforming growth factors (beta), including beta-1, beta-2, beta-3,inhibin, activin, and DNA that encodes for the production of any ofthese proteins, antisense molecules, androgenic receptor blockers andstatin agents.

In an embodiment, the active agent used with the invention includescompounds having a steroid ring system. Compounds having a steroid ringsystem can be referred to as steroids. In an embodiment, the activeagent is a steroid. Steroids include both naturally occurring compoundsand synthetic analogues based on the cyclopenta[a]phenanthrene carbonskeleton, partially or completely hydrogenated. Steroids can includeglucocorticoids, estrogens and androgens. By way of example, steroidscan include dexamethasone, dexamethasone acetate, dexamethasone sodiumphosphate, cortisone, cortisone acetate, hydrocortisone, hydrocortisoneacetate, hydrocortisone cypionate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, prednisone, prednisolone, prednisoloneacetate, prednisolone sodium phosphate, prednisolone tebutate,prednisolone pivalate, triamcinolone, triamcinolone acetonide,triamcinolone hexacetonide, triamcinolone diacetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,flunsolide, beclomethasone dipropionate, betamethasone sodium phosphate,betamethasone, vetamethasone disodium phosphate, vetamethasone sodiumphosphate, betamethasone acetate, betamethasone disodium phosphate,chloroprednisone acetate, corticosterone, desoxycorticosterone,desoxycorticosterone acetate, desoxycorticosterone pivalate,desoximethasone, estradiol, fludrocortisone, fludrocortisone acetate,dichlorisone acetate, fluorohydrocortisone, fluorometholone,fluprednisolone, paramethasone, paramethasone acetate, androsterone,fluoxymesterone, aldosterone, methandrostenolone, methylandrostenediol,methyl testosterone, norethandrolone, testosterone, testosteroneenanthate, testosterone propionate, equilenin, equilin, estradiolbenzoate, estradiol dipropionate, estriol, estrone, estrone benzoate,acetoxypregnenolone, anagestone acetate, chlormadinone acetate,flurogestone acetate, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, hydroxyprogesterone,hydroxyprogesterone acetate, hydroxyprogesterone caproate, melengestrolacetate, normethisterone, pregnenolone, progesterone, ethynyl estradiol,mestranol, dimethisterone, ethisterone, ethynodiol diacetate,norethindrone, norethindrone acetate, norethisterone, fluocinoloneacetonide, flurandrenolone, hydrocortisone sodium succinate,methylprednisolone sodium succinate, prednisolone phosphate sodium,triamcinolone acetonide, hydroxydione sodium, spironolactone,oxandrolone, oxymetholone, prometholone, testosterone cypionate,testosterone phenylacetate, estradiol cypionate, and norethynodrel,analogs thereof, or combinations thereof.

Active agents used with the invention can include macromolecules, smallmolecules, hydrophilic molecules, hydrophobic molecules, and the like.Macromolecular active agents used with embodiments of the invention caninclude proteins, nucleic acids, and polysaccharides. By way of example,proteins can include glycosylated proteins, antibodies (both monoclonaland polyclonal), antibody derivatives (including diabodies, f(ab)fragments, humanized antibodies, etc.), cytokines, growth factors,receptor ligands, enzymes, and the like. Nucleic acids can include RNA,DNA, cDNA, and the like.

In an embodiment, macromolecular active agents used with the inventionhave a molecular weight (or average molecular weight) of greater thanabout 10 kD (1 kilodalton is equal to 1,000 atomic mass units). In anembodiment, the macromolecular active agent includes a protein ofgreater than about 10 kD. In an embodiment, the macromolecular activeagent includes a protein of greater than about 100 kD.

In some embodiments, the active agent of the coating can include agentsthat are small molecules. In some embodiments, the active agent caninclude therapeutic agents that are hydrophilic small molecules. In someembodiments, the active agent can include therapeutic agents that arehydrophobic small molecules. As used herein, small molecules can includethose with a molecular weight of equal to or less than 10 kilodaltons.In an embodiment, small molecules have a molecular weight of less thanabout 5 kilodaltons.

By way of example, small molecule active agents can include TrigonellineHCL, diclofenac, and chlorhexidine diacetate. Small molecules caninclude many types of therapeutics including those as described abovewith respect to macromolecules (e.g., thrombin inhibitors,antithrombogenic agents, etc.).

The weight of the coating attributable to the active agent can be in anyrange desired for a given active agent in a given application. In someembodiments, weight of the coating attributable to the active agent isin the range of about 1 microgram to about 10 milligrams of active agentper cm² of the effective surface area of the device. By “effective”surface area it is meant the surface amenable to being coated with thecomposition itself. For a flat, nonporous, surface, for instance, thiswill generally be the macroscopic surface area itself, while forconsiderably more porous or convoluted (e.g., corrugated, pleated, orfibrous) surfaces the effective surface area can be significantlygreater than the corresponding macroscopic surface area. In anembodiment, the weight of the coating attributable to the active agentis between about 0.01 mg and about 0.5 mg of active agent per cm² of thegross surface area of the device. In an embodiment, the weight of thecoating attributable to the active agent is greater than about 0.01 mg.

In some embodiments, more than one active agent can be used as a part ofthe coating material. Specifically, co-agents or co-drugs can be used. Aco-agent or co-drug can act differently than the first agent or drug.The co-agent or co-drug can have an elution profile that is differentthan the first agent or drug. In some embodiments, accessory agents areincluded such as chaperonins.

Devices

Embodiments of the invention can be used to coat many different types ofdevices including medical devices. Medical devices can include bothimplantable devices and non-implantable medical devices.

Embodiments of the invention can be used with implantable, ortransitorily implantable, devices including, but not limited to,vascular devices such as grafts (e.g., abdominal aortic aneurysm grafts,etc.), stents (e.g., self-expanding stents typically made from nitinol,balloon-expanded stents typically prepared from stainless steel,degradable coronary stents, etc.), catheters (including arterial,intravenous, blood pressure, stent graft, etc.), valves (e.g., polymericor carbon mechanical valves, tissue valves, valve designs includingpercutaneous, sewing cuff, and the like), embolic protection filters(including distal protection devices), vena cava filters, aneurysmexclusion devices, artificial hearts, cardiac jackets, and heart assistdevices (including left ventricle assist devices), implantabledefibrillators, electro-stimulation devices and leads (includingpacemakers, lead adapters and lead connectors), implanted medical devicepower supplies (e.g., batteries, etc.), peripheral cardiovasculardevices, atrial septal defect closures, left atrial appendage filters,valve annuloplasty devices (e.g., annuloplasty rings), mitral valverepair devices, vascular intervention devices, ventricular assist pumps,and vascular access devices (including parenteral feeding catheters,vascular access ports, central venous access catheters); surgicaldevices such as sutures of all types, staples, anastomosis devices(including anastomotic closures), suture anchors, hemostatic barriers,screws, plates, clips, vascular implants, tissue scaffolds,cerebro-spinal fluid shunts, shunts for hydrocephalus, drainage tubes,catheters including thoracic cavity suction drainage catheters, abscessdrainage catheters, biliary drainage products, and implantable pumps;orthopedic devices such as joint implants, acetabular cups, patellarbuttons, bone repair/augmentation devices, spinal devices (e.g.,vertebral disks and the like), bone pins, cartilage repair devices, andartificial tendons; dental devices such as dental implants and dentalfracture repair devices; drug delivery devices such as drug deliverypumps, implanted drug infusion tubes, drug infusion catheters, andintravitreal drug delivery devices; ophthalmic devices including orbitalimplants, glaucoma drain shunts and intraocular lenses; urologicaldevices such as penile devices (e.g., impotence implants), sphincter,urethral, prostate, and bladder devices (e.g., incontinence devices,benign prostate hyperplasia management devices, prostate cancerimplants, etc.), urinary catheters including indwelling (“Foley”) andnon-indwelling urinary catheters, and renal devices; syntheticprostheses such as breast prostheses and artificial organs (e.g.,pancreas, liver, lungs, heart, etc.); respiratory devices including lungcatheters; neurological devices such as neurostimulators, neurologicalcatheters, neurovascular balloon catheters, neuro-aneurysm treatmentcoils, and neuropatches; ear nose and throat devices such as nasalbuttons, nasal and airway splints, nasal tampons, ear wicks, eardrainage tubes, tympanostomy vent tubes, otological strips, laryngectomytubes, esophageal tubes, esophageal stents, laryngeal stents, salivarybypass tubes, and tracheostomy tubes; biosensor devices includingglucose sensors, cardiac sensors, intra-arterial blood gas sensors;oncological implants; and pain management implants.

Classes of suitable non-implantable devices can include dialysis devicesand associated tubing, catheters, membranes, and grafts; autotransfusiondevices; vascular and surgical devices including atherectomy catheters,angiographic catheters, intraaortic balloon pumps, intracardiac suctiondevices, blood pumps, blood oxygenator devices (including tubing andmembranes), blood filters, blood temperature monitors, hemoperfusionunits, plasmapheresis units, transition sheaths, dialators, intrauterinepressure devices, clot extraction catheters, percutaneous transluminalangioplasty catheters, electrophysiology catheters, breathing circuitconnectors, stylets (vascular and non-vascular), coronary guide wires,peripheral guide wires; dialators (e.g., urinary, etc.); surgicalinstruments (e.g. scalpels and the like); endoscopic devices (such asendoscopic surgical tissue extractors, esophageal stethoscopes); andgeneral medical and medically related devices including blood storagebags, umbilical tape, membranes, gloves, surgical drapes, wounddressings, wound management devices, needles, percutaneous closuredevices, transducer protectors, pessary, uterine bleeding patches, PAPbrushes, clamps (including bulldog clamps), cannulae, cell culturedevices, materials for in vitro diagnostics, chromatographic supportmaterials, infection control devices, colostomy bag attachment devices,birth control devices; disposable temperature probes; and pledgets.

In some aspects, embodiments of the invention can be utilized inconnection with ophthalmic devices. Suitable ophthalmic devices inaccordance with these aspects can provide bioactive agent to any desiredarea of the eye. In some aspects, the devices can be utilized to deliverbioactive agent to an anterior segment of the eye (in front of thelens), and/or a posterior segment of the eye (behind the lens). Suitableophthalmic devices can also be utilized to provide bioactive agent totissues in proximity to the eye, when desired.

In some aspects, embodiments of the invention can be utilized inconnection with ophthalmic devices configured for placement at anexternal or internal site of the eye. Suitable external devices can beconfigured for topical administration of bioactive agent. Such externaldevices can reside on an external surface of the eye, such as the cornea(for example, contact lenses) or bulbar conjunctiva. In someembodiments, suitable external devices can reside in proximity to anexternal surface of the eye.

Devices configured for placement at an internal site of the eye canreside within any desired area of the eye. In some aspects, theophthalmic devices can be configured for placement at an intraocularsite, such as the vitreous. Illustrative intraocular devices include,but are not limited to, those described in U.S. Pat. No. 6,719,750 B2(“Devices for Intraocular Drug Delivery,” Varner et al.) and U.S. Pat.No. 5,466,233 (“Tack for Intraocular Drug Delivery and Method forInserting and Removing Same,” Weiner et al.); U.S. Publication Nos.2005/0019371 A1 (“Controlled Release Bioactive Agent Delivery Device,”Anderson et al.), 2004/0133155 A1 (“Devices for Intraocular DrugDelivery,” Varner et al.), 2005/0059956 A1 (“Devices for IntraocularDrug Delivery,” Varner et al.), and 2003/0014036 A1 (“Reservoir Devicefor Intraocular Drug Delivery,” Varner et al.); and U.S. applicationSer. No. 11/204,195 (filed Aug. 15, 2005, Anderson et al.), Ser. No.11/204,271 (filed Aug. 15, 2005, Anderson et al.), Ser. No. 11/203,981(filed Aug. 15, 2005, Anderson et al.), Ser. No. 11/203,879 (filed Aug.15, 2005, Anderson et al.), Ser. No. 11/203,931 (filed Aug. 15, 2005,Anderson et al.); and related applications.

In some aspects, the ophthalmic devices can be configured for placementat a subretinal area within the eye. Illustrative ophthalmic devices forsubretinal application include, but are not limited to, those describedin U.S. Patent Publication No. 2005/0143363 (“Method for SubretinalAdministration of Therapeutics Including Steroids; Method for LocalizingPharmacodynamic Action at the Choroid and the Retina; and RelatedMethods for Treatment and/or Prevention of Retinal Diseases,” de Juan etal.); U.S. application Ser. No. 11/175,850 (“Methods and Devices for theTreatment of Ocular Conditions,” de Juan et al.); and relatedapplications.

Suitable ophthalmic devices can be configured for placement within anydesired tissues of the eye. For example, ophthalmic devices can beconfigured for placement at a subconjunctival area of the eye, such asdevices positioned extrasclerally but under the conjunctiva, such asglaucoma drainage devices and the like.

The present invention may be better understood with reference to thefollowing examples. These examples are intended to be representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

EXAMPLES Example 1 Preparation of Coating SolutionsSaturated/Unsaturated

Coating solutions were prepared with various concentrations of drug,polymers, and solvents. Specifically, five different coating solutionswere prepared as follows (the coating solutions are summarized in Table1 below):

Solution 1: Estradiol was combined with THF (tetrahydrofuran) to form anactive agent solution. PEVA (polyethylene-co-vinyl acetate, 33% vinylacetate) and PBMA (poly-n-butyl methacrylate) were combined with tolueneto form a polymer solution. The active agent solution and the toluenesolution were combined to form a coating solution having 40 mg/ml totalsolids including 30 wt. % estradiol, 20 wt. % PEVA, and 50 wt. % PBMA ina solvent of 80% toluene and 20% THF (four parts toluene to one partTHF). The coating solution was allowed to stand for a period of minutesat ambient temperature and was observed to be clear, indicating that theestradiol was at a soluble concentration for this solvent composition.

Solution 2: Estradiol was combined with THF (tetrahydrofuran) to form anactive agent solution. PEVA (polyethylene-co-vinyl acetate, 33% vinylacetate) and PBMA (poly-n-butyl methacrylate) were combined with tolueneto form a polymer solution. The active agent solution and the toluenesolution were combined to form a coating solution having 40 mg/ml totalsolids including 30 wt. % estradiol, 20 wt. % PEVA, and 50 wt. % PBMA ina solvent of 85% toluene and 15% THF. The coating solution was allowedto stand for a period of minutes at ambient temperature and crystalformation was observed, indicating that the estradiol was at aconcentration exceeding solubility limits for this solvent composition.

Solution 3: Estradiol was combined with THF (tetrahydrofuran) to form anactive agent solution. PEVA (polyethylene-co-vinyl acetate, 33% vinylacetate) and PBMA (poly-n-butyl methacrylate) were combined with tolueneto form a polymer solution. The active agent solution and the toluenesolution were combined to form a coating solution having 40 mg/ml totalsolids including 40 wt. % estradiol, 20 wt. % PEVA, and 40 wt. % PBMA ina solvent of 80% toluene and 20% THF. The coating solution was allowedto stand for a period of minutes at ambient temperature and crystalformation was observed, indicating that the estradiol was at aconcentration exceeding solubility limits for this solvent composition.

Solution 4: Estradiol was combined with THF (tetrahydrofuran) to form anactive agent solution. PEVA (polyethylene-co-vinyl acetate, 33% vinylacetate) and PBMA (poly-n-butyl methacrylate) were combined with tolueneto form a polymer solution. The active agent solution and the polymersolution were combined to form a coating solution having 40 mg/ml totalsolids including 35 wt. % estradiol, 20 wt. % PEVA, and 45 wt. % PBMA ina solvent of 80% toluene and 20% THF. The coating solution was allowedto stand for a period of minutes at ambient temperature and crystalformation was observed, indicating that the estradiol was at aconcentration exceeding solubility limits for this solvent composition.

Solution 5: Estradiol was combined with THF (tetrahydrofuran) to form anactive agent solution. PEVA (polyethylene-co-vinyl acetate, 33% vinylacetate) and PBMA (poly-n-butyl methacrylate) were combined with tolueneto form a polymer solution. The active agent solution and the toluenesolution were combined to form a coating solution having 40 mg/ml totalsolids including 32.5 wt. % estradiol, 20 wt. % PEVA, and 47.5 wt. %PBMA in a solvent of 80% toluene and 20% THF. The coating solution wasallowed to stand for a period of minutes at ambient temperature and thestart of a small amount of crystal formation was observed, indicatingthat the estradiol was at a concentration slightly exceeding solubilitylimits for this solvent composition.

TABLE 1 Solids (40 mg/ml) Solvent Solution Estradiol (wt. %) PEVA (wt.%) PBMA (wt. %) toluene THF Result 1 30.0 20.0 50.0 80 20 no crystals 230.0 20.0 50.0 85 15 many crystals 3 40.0 20.0 40.0 80 20 many crystals4 35.0 20.0 45.0 80 20 many crystals 5 32.5 20.0 47.5 80 20 somecrystals

This example demonstrates that at a total solids concentration of 40mg/ml the solubility limit of estradiol is somewhere between 30.0 wt. %and 32.5 wt. % at ambient temperature (approximately 21-22° C.) for asolvent including 80% toluene and 20% THF. This is equivalent to asolubility limit of between about 12 mg/ml and about 13 mg/ml ofestradiol in a solvent including 80% toluene and 20% THF in the presenceof PEVA and PBMA.

Example 2 Non-Saturated Coating Composition with THF/IPA Solvent

Estradiol, polyethylene-co-vinyl acetate (PEVA) (33% vinyl acetate), andpoly-n-butyl methacrylate (PBMA) were combined in equal weightproportions in a solution that was 90% tetrahydrofuran (THF) and 10%isopropyl alcohol (IPA). The resulting solution had a total solidsconcentration of 40 mg/ml (33% PEVA/33% PBMA/33% estradiol). Theresulting solution was below the saturation point for estradiol in asolvent of 90% THF/10% IPA at ambient temperature (approximately 21-22°C.).

A stainless steel stent 18 mm in length was obtained and prepared byfirst applying a layer of parylene C using a vapor-deposition technique.After the parylene was disposed onto the stent, the coating solution wasapplied to the stent using an ultrasonic spray technique at a relativehumidity of 10%. Ultrasonic spray techniques are disclosed in U.S.Published Application 2004/0062875 (Chappa et al.) the contents of whichare herein incorporated by reference. A total coating weight of 657 μgwas applied to the stent (measured after the solvent had substantiallyevaporated off) resulting in a drug loading of approximately 217 μg ofestradiol.

On day 0 (the day the coating was applied), optical microscopy was usedwith polarized light to evaluate the surface of the stent. The polarizedlight image shows the formation of crystals of active agent not just atthe surface of the coating but throughout the coating thickness. FIG. 1shows the coating at Day 0. It was estimated that approximately 50% ofthe coating contained active agent crystals. On day 4, opticalmicroscopy was again used with polarized light to evaluate the coating.FIG. 2 shows the stent surface at Day 4. It was estimated thatapproximately 95% of coating contained active agent crystals.

After 7 days, the surface of the stent was examined using scanningelectron microscopy (SEM) at various magnifications. A 7500× view isshown in FIG. 3. SEM analysis revealed that there were significantquantities of active agent crystals coming out of the surface of thecoating.

This example shows that when a coating solution is applied wherein theconcentration of the active agent is below the saturation point, thecrystallization process may take place over an extended period of time.

Example 3 Non-Saturated Coating Composition with Chloroform/MethanolSolvent

Estradiol, polyethylene-co-vinyl acetate (PEVA) (33% vinyl acetate), andpoly-n-butyl methacrylate (PBMA) were combined in equal weightproportions in a solution that was 80% chloroform and 20% methanol. Theresulting solution had a total solids concentration of 40 mg/ml (33%PEVA/33% PBMA/33% estradiol). The resulting solution was below thesaturation point for estradiol in a solvent of 80% chloroform/20%methanol at ambient temperature (approximately 21-22° C.).

A stainless steel stent 18 mm in length was obtained and prepared byfirst applying a layer of parylene C using a vapor-deposition technique.After the parylene was disposed onto the stent, the coating solution wasapplied to the stent using an ultrasonic spray technique. A totalcoating weight of 683 μg was applied to the stent (measured after thesolvent had substantially evaporated off) resulting in a drug loading ofapproximately 225 μg of estradiol.

After 8 days, the surface of the stent was examined using scanningelectron microscopy (SEM) at various magnifications. A 7500× view isshown in FIG. 4. SEM analysis revealed that there were significantquantities of crystals coming out of the surface of the coating.

Example 4 Saturated Coating Composition with Toluene/THF/IsopropylAlcohol Solvent

Estradiol was combined with THF. Polyethylenevinylacetate (PEVA), andpoly-n-butyl methacrylate (PBMA) was combined with a solution containingeight parts toluene and one part isopropyl alcohol. The estradiolsolution was combined with the PEVA/PBMA solution to form a coatingsolution containing equal weight proportions of estradiol, PEVA, andPBMA and a solvent containing 80% toluene, 10% THF, and 10% isopropylalcohol, with a total solids concentration of 40 mg/ml (33% PEVA/33%PBMA/33% estradiol). The resulting solution was approximately at thesaturation point for estradiol in a solvent of 80% toluene, 10% THF, and10% isopropyl alcohol at ambient temperature (approximately 21-22° C.).

Two stainless steel stents (A and B) 18 mm in length were obtained andprepared by first applying a layer of parylene C using avapor-deposition technique. After the parylene was disposed onto thestents, the coating solution was applied to the stent using anultrasonic spray technique at a relative humidity of 10%. A totalcoating weight of 688 μg was applied to stent A (measured after thesolvent had substantially evaporated off) resulting in a drug loading ofapproximately 227 μg of estradiol. A total coating weight of 659 μg wasapplied to stent B (measured after the solvent had substantiallyevaporated off) resulting in a drug loading of approximately 217 μg ofestradiol.

After the coating process was completed, stent B was evaluated forcrystal formation using darkfield microscopy. Darkfield microscopy showsthe formation of crystals not just at the surface of the coating butthroughout the coating thickness. FIG. 5 shows a darkfield image of thecoating on stent B. This darkfield image shows active agent crystalsover substantially 100% of the coating (within the coating). In contrastto FIG. 1 in example 2 above, this example demonstrates that rapidcrystallization occurs when using a saturated coating solution.

After 7 days, the surface of stent A was examined using scanningelectron microscopy (SEM) at various magnifications. A 7500× view isshown in FIG. 6. SEM analysis revealed that there was crystal formationbut that these crystals did not come out of, or erupt, through thesurface of the coating.

This example shows that applying a coating solution that was saturatedwith the active agent reduced the amount of crystals that eruptedthrough the surface of the coating.

Example 5 Saturated Coating Composition with Toluene/THF Solvent

Estradiol was combined with THF. Two parts by weight ofpolyethylenevinylacetate (PEVA) was combined with five parts by weightof poly-n-butyl methacrylate (PBMA) in toluene. The estradiol solutionwas combined with the PEVA/PBMA solution to form a coating solutioncontaining 40 mg/ml total solids (30 wt. % estradiol, 20 wt. % PEVA, and50 wt. % PBMA) and a solvent containing 80% toluene and 20% THF. Theresulting solution was near the saturation point for estradiol in asolvent of 80% toluene and 20% THF at ambient temperature (approximately21-22° C.).

A stainless steel stent 28 mm in length was obtained and prepared byfirst applying a layer of parylene C using a vapor-deposition technique.After the parylene was disposed onto the stent, the coating solution wasapplied to the stent using an ultrasonic spray technique at a relativehumidity of 30%. A total coating weight of 2015 μg was applied to thestent (measured after the solvent had substantially evaporated off)resulting in a drug loading of approximately 605 μg of estradiol.

After 7 days, the surface of the stent was examined using scanningelectron microscopy (SEM) at various magnifications. FIG. 7 shows thesurface of the coating at 500× magnification. SEM analysis revealed thatthe surface was somewhat bumpy but that there were substantially nocrystals coming out of, or erupting through, the surface of the coating.

This example shows that applying a coating solution that is saturatedwith the active agent (or near saturation) can reduce the amount ofcrystals that erupt through the surface of the coating.

Example 6 Unsaturated Coating Composition with Toluene/THF Solvent

Estradiol was combined with THF. Two parts by weight ofpolyethylenevinylacetate (PEVA) was combined with five parts by weightof poly-n-butyl methacrylate (PBMA) in toluene. The estradiol solutionwas combined with the PEVA/PBMA solution to form a coating solutioncontaining 30 mg/ml total solids (30 wt. % estradiol, 20 wt. % PEVA, and50 wt. % PBMA) and a solvent containing 80% toluene and 20% THF. Theresulting solution had an estradiol concentration that was less than thesaturation point for a solvent of 80% toluene and 20% THF at ambienttemperature (approximately 21-22° C.). The distinction between thisexample and example 4 is that here the total solids concentration wasonly 30 mg/ml instead of 40 mg/ml. Thus the concentration of estradiolwas at less than the saturation point.

A stainless steel stent 28 mm in length was obtained and prepared byfirst applying a layer of parylene C using a vapor-deposition technique.After the parylene was disposed onto the stent, the coating solution wasapplied to the stent using an ultrasonic spray technique at a relativehumidity of 30%. A total coating weight of 1000 μg was applied to thestent (measured after the solvent had substantially evaporated off)resulting in a drug loading of approximately 300 μg of estradiol. Thecoating was evaluated under a microscope at 50× magnification (notshown). The coating had a patchy appearance and the formation of largecrystals was observed. This coating had an appearance similar to thatwhich could be observed with other non-saturated solutions such as inExamples 2 and 3 above.

This example shows that when a coating solution is applied wherein theconcentration of the active agent is below the saturation point, thecrystallization process may result in the formation of large crystals.

Example 7 Non-Saturated Coating Composition with THF Solvent and Topcoat

Estradiol, polyethylenevinylacetate (PEVA), and poly-n-butylmethacrylate (PBMA) were combined in THF to result in weight proportionsof 30% estradiol, 20% PEVA, and 50% PBMA for a total solidsconcentration of 40 mg/ml. The resulting solution had a estradiolconcentration that was less than the saturation point for a solvent of100% THF at ambient temperature (approximately 21-22° C.).

A stainless steel stent 9 mm in length was obtained and prepared byfirst applying a layer of parylene C using a vapor-deposition technique.After the parylene was disposed onto the stent, the coating solution wasapplied to the stent using an ultrasonic spray technique at a relativehumidity of 30%. A total coating weight of 615 μg was applied to thestent (measured after the solvent had substantially evaporated off)resulting in a drug loading of approximately 185 μg of estradiol.

Next, a topcoat solution was formed by mixing PBMA with THF to form asolution with a total solids concentration of 10 mg/ml. The topcoatsolution was applied to the stent using an ultrasonic spray technique ata relative humidity of 30%, resulting in a topcoat weight of 107 μg(measured after the solvent had substantially evaporated off).

After 7 days, the surface of the stent was examined using scanningelectron microscopy (SEM) at various magnifications. FIG. 8 shows a viewof the topcoat surface at 1000× magnification. SEM analysis revealedthat there were significant amounts of crystals coming out of, orerupting through, the surface of the topcoat.

This example shows that when a coating solution is applied wherein theconcentration of the active agent is below the saturation point, evenwhere a topcoat is added, the crystallization process can result incrystals of the active agent erupting through the coating surface.

Example 8 Saturated Coating Composition with Toluene/THF Solvent andTopcoat

Estradiol was combined with THF. Two parts by weight ofpolyethylenevinylacetate (PEVA) was combined with five parts by weightof poly-n-butyl methacrylate (PBMA) in toluene. The estradiol solutionwas combined with the PEVA/PBMA solution to form a coating solutioncontaining 40 mg/ml total solids (30 wt. % estradiol, 20 wt. % PEVA, and50 wt. % PBMA) and a solvent containing 80% toluene and 20% THF. Theresulting solution was approximately at the saturation point forestradiol in a solvent of 80% toluene and 20% THF at ambient temperature(approximately 21-22° C.).

A stainless steel stent 28 mm in length was obtained and prepared byfirst applying a layer of parylene C using a vapor-deposition technique.After the parylene was disposed onto the stent, the coating solution wasapplied to the stent using an ultrasonic spray technique at a relativehumidity of 30%. A total coating weight of 2094 μg was applied to thestent (measured after the solvent had substantially evaporated off)resulting in a drug loading of approximately 629 μg of estradiol.

Next, a topcoat solution was formed by mixing PBMA with toluene to forma solution with a total solids concentration of 30 mg/ml. The topcoatsolution was applied to the stent using an ultrasonic spray technique ata relative humidity of 10%, resulting in a topcoat weight of 297 μg(measured after the solvent had substantially evaporated off).

After 7 days, the surface of the stent was examined using scanningelectron microscopy (SEM) at various magnifications. FIG. 9 shows thesurface of the topcoat at 1000× magnification. SEM analysis revealedthat there were substantially no crystals coming out of, or eruptingthrough, the surface of the coating.

This example shows that applying a coating solution that is saturatedwith the active agent can reduce the amount of crystals that eruptthrough the surface of the coating.

Example 9 Saturated Versus Unsaturated Coating Compositions IncludingDexamethasone

To form a saturated coating solution (solution one), dexamethasone (DEX)was combined with polybutadiene (PBD) (MW 160 kD) and poly(n-butylmethacrylate) (pBMA) (MW 250 kD) in a solvent mixture of 58% THF and 42%chloroform. The saturated coating solution was made by adding 75 mg ofpBMA and 75 mg of PBD to 5 ml of chloroform on a stir-plate. To thissolution, 150 mg of DEX was added. THF was slowly added to the stirringmixture until the resulting solution turned clear. A total of 7 ml ofTHF was added. The resulting coating solution had a total solids contentof 25 mg/ml including (50% DEX), (25% PBD), and (25% pBMA).

To form an unsaturated control coating solution (solution two), DEX wascombined with polybutadiene (PBD) (MW 160 kD) and poly(n-butylmethacrylate) (pBMA) (MW 250 kD) in a solvent of 100% tetrahydrofuran(THF). The resulting coating solution had a total solids content of 25mg/ml including (50% DEX), (25% PBD), and (25% pBMA).

Four stainless steel stents (OrbusNeich, Netherlands) 18 mm in lengthwere obtained. Coating solution one was applied to two stents (1 and 2)using an ultrasonic spray technique at a relative humidity of 30%.Similarly, coating solution two was applied to two stents (3 and 4)using an ultrasonic spray technique at a relative humidity of 30%.

The surface of the stents was examined using polarized light opticalmicroscopy at days 0, 7, and 14. Polarized light microscopy shows theamount of crystallization throughout the entire coating thickness. FIG.10, panels A, B, and C, show a representative portion of stent 1(saturated) at 100× magnification. FIG. 10, panel A, shows that on day0, stent 1 was approximately 100% crystallized. FIG. 10, panels B and Cshow that stent 1 remained approximately 100% crystallized on days 7 and14 respectively. FIG. 10, panels D, E, and F, show a representativeportion of stent 3 (unsaturated) at 100× magnification. FIG. 10, panelD, shows that on day 0, stent 3 was roughly 10% crystallized. FIG. 10,panels E and F, show that the degree of crystallization on stent 3increased over a period of two weeks but remained less than 50%crystallized. A similar pattern was demonstrated when comparing thecrystallization trends of stents 2 (saturated) and 4 (unsaturated).

Portions stents 2 and 4 that had crystals were then evaluated usingpolarized light optical microscopy at a higher magnification (500×) tofurther characterize the differences between the two. The results areshown in FIG. 11, panels A and B. The crystals in panel A (formed from asaturated coating solution) are clearly smaller than those shown inpanel B (formed from an unsaturated coating solution).

This example shows that saturated coating solutions can be used toenhance the formation of active agent crystals in the resulting coating.Specifically, this example shows that saturated coating solutions can beused to accelerate the crystallization process in elution controlcoatings. This example also shows that the use of saturated coatingsolutions results in smaller more uniform crystals than does the use ofunsaturated coating solutions.

It should be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to a composition containing “a compound” includes a mixture oftwo or more compounds. It should also be noted that the term “or” isgenerally employed in its sense including “and/or” unless the contentclearly dictates otherwise.

It should also be noted that, as used in this specification and theappended claims, the phrase “configured” describes a system, apparatus,or other structure that is constructed or configured to perform aparticular task or adopt a particular configuration to. The phrase“configured” can be used interchangeably with other similar phrases suchas arranged and configured, constructed and arranged, constructed,manufactured and arranged, and the like.

All publications and patent applications in this specification areindicative of the level of ordinary skill in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated by reference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A method for enhancing crystallization of an active agent in acoating disposed on a medical device, the method comprising: selecting asolvent and a hydrophobic polymer, wherein the polymer and solvent forma true solution; selecting a concentration of an active agent selectedfrom the group consisting of paclitaxel, rapamycin, rapalogs, andderivatives thereof wherein the concentration of active agent is atleast 80% of saturation in a composition comprising the solvent andabout 1.0 to about 99.0 wt. % polymer; combining the active agent, thepolymer, and the solvent to form a coating composition having theselected concentration of the active agent; applying the coatingcomposition to the medical device; and evaporating the solvent to formcrystals of the active agent.
 2. The method of claim 1, comprisingselecting a concentration of the active agent that is at least 90% ofsaturation in a composition comprising the solvent and about 1.0 toabout 99.0 wt. % polymer.
 3. The method of claim 1, comprising selectinga concentration of the active agent that is at least 95% of saturationin a composition comprising the solvent and about 1.0 to about 99.0 wt.% polymer.
 4. The method of claim 1, comprising selecting aconcentration of the active agent that is at least 99% of saturation ina composition comprising the solvent and about 1.0 to about 99.0 wt. %polymer.
 5. The method of claim 1, the active agent comprisingpaclitaxel.
 6. The method of claim 1, the active agent comprisingrapamycin.
 7. The method of claim 1, the solvent comprising a firstsolvent and a second solvent; wherein the active agent is soluble in thefirst solvent and insoluble in the second solvent.
 8. The method ofclaim 7, the first solvent having a higher vapor pressure than thesecond solvent.
 9. The method of claim 1, the first solvent comprisingTHF and the second solvent comprising toluene.
 10. The method of claim1, the polymer comprises a first polymer component comprising at leastone poly(alkyl)(meth)acrylate and a second polymer component comprisingpoly(ethylene-co-vinyl acetate), wherein the second polymer component isselected from the group consisting of poly(ethylene-co-vinyl acetate)polymers having vinyl acetate concentrations of between about 10% andabout 50% by weight.
 11. The method of claim 1, wherein the polymercomprises a first polymer component comprising at least onepoly(alkyl)(meth)acrylate and a second polymer component comprisingpolybutadiene.
 12. An elution control coating disposed on a medicaldevice, the elution control coating comprising: a hydrophobic polymer,and an active agent selected from the group consisting of paclitaxel,rapamycin, rapalogs, and derivatives thereof, wherein the active agentis at least 80% crystallized within one week of being disposed on themedical device.
 13. The elution control coating of claim 12, wherein theactive agent is at least 90% crystallized within one week of beingdisposed on the medical device.
 14. The elution control coating of claim12, wherein the active agent is at least 95% crystallized within oneweek of being disposed on the medical device.
 15. The elution controlcoating of claim 12, wherein the active agent is at least 95%crystallized within one day of being disposed on the medical device. 16.The elution control coating of claim 12, the active agent comprisingpaclitaxel.
 17. The elution control coating of claim 12, the activeagent comprising rapamycin.
 18. The elution control coating of claim 12,the polymer comprises a first polymer component comprising at least onepoly(alkyl)(meth)acrylate and a second polymer component comprisingpoly(ethylene-co-vinyl acetate), wherein the second polymer component isselected from the group consisting of poly(ethylene-co-vinyl acetate)polymers having vinyl acetate concentrations of between about 10% andabout 50% by weight.
 19. The elution control coating of claim 12, thepolymer comprises a first polymer component comprising at least onepoly(alkyl)(meth)acrylate and a second polymer component comprisingpoly(ethylene-co-vinyl acetate), wherein the second polymer component isselected from the group consisting of poly(ethylene-co-vinyl acetate)polymers having vinyl acetate concentrations of between about 10% andabout 50% by weight.
 20. The elution control coating of claim 12, thepolymer comprises a first polymer component comprising at least onepoly(alkyl)(meth)acrylate and a second polymer component comprisingpolybutadiene.
 21. A method for enhancing the formation of active agentcrystals within a coating layer comprising: combining a polymer, anactive agent, and a solvent to form a coating solution comprisingbetween 5 mg/ml and 200 mg/ml total solids concentration; adjusting theconcentration of the active agent in the coating solution to reach atleast 80% of the active agent saturation point; applying the coatingsolution to a device; and evaporating the solvent to form crystals ofthe active agent.
 22. (canceled)